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Antipsychotics are getting pushback as a treatment for behavioral symptoms in AD patients. While at first blush it may seem reasonable to use these drugs to control psychiatric symptoms in moderate and advanced dementia, prior studies have warned of serious side effects (see ARF related news story), limited efficacy (see ARF related news story), and in short-term (8-12 week) trials even increased mortality in AD patients taking second-generation antipsychotics (see ARF related news story). That deadly risk is now confirmed by results from the much longer dementia antipsychotic withdrawal trial (DART-AD), published in today’s Lancet Neurology online. Led by Clive Ballard at King’s College London, DART-AD investigators found that over a period of 12 months, patients continuing on drug instead of placebo had a significantly increased rate of mortality. The authors write that “...the accumulating safety concerns, including the substantial increase in long-term mortality, emphasise the urgent need to put an end to unnecessary and prolonged prescribing.”

Ballard and colleagues randomized 165 AD patients living in care facilities in the U.K. to either continue their use of antipsychotic treatment (at enrollment patients had to have been taking such a drug for three months) or to take a placebo for 12 months. At the end of the randomized period, the probability of survival in the drug group was 90 percent, compared to 97 percent in the placebo group. The researchers also followed patients for up to three and a half years after the trial, finding even more pronounced differences in mortality. At 24 months, survival was 46 and 71 percent in drug and placebo groups, respectively, and the differences were even greater at 36 and 54 months. The authors write that it is not clear why the biggest differences in mortality occur after the 12-month trial. One plausible explanation is that the frailest patients are most likely to die within the first 12 months regardless of medication status. Another possibility is that the close monitoring of patients during the trial helped prevent fatalities. Whatever the reason, the hazard ratio for survival over the full study (54 months) was 0.58 in the drug group compared to placebo, meaning people were a little over half as likely to still be alive if they had been on antipsychotic drugs than if they had been on placebo.

“This work further emphasises the clinical imperative to review antipsychotic medication that is regularly prescribed, and to avoid a protracted period of treatment with antipsychotic drugs in people with dementia,” write the authors. In fact, the U.S. Food and Drug Administration is aware of the increased mortality in AD patients treated with antipsychotics and has issued a black box warning to that effect, also noting that the drugs are not approved for AD (see FDA public health advisory). Nevertheless, some clinicians see antipsychotics as an important part and parcel of AD management and are not convinced that the clinical trial data capture the full story. John (Wes) Ashford, a psychiatrist at Stanford University, California, has reported that AD patients are the most violent of all psychiatric patients (see Paveza et al., 1992) and he wrote ARF via e-mail, “the most agitated patients need to be managed acutely and cannot participate in such trials.” For this reason he believes that real-life, placebo-controlled trials of antipsychotic medications cannot be conducted (see full comment below). In fact, Ballard and colleagues concede that this is a limitation of their study. Enrollment required a Mini-Mental State Exam score of 6 or more and a Severe Impairment Battery score of 30 or more, effectively eliminating the most severely affected patients.

And even if there is increased risk of mortality, might these drugs offer some relief for this terminal illness over the short term if managed properly? As Ashford wrote, “…isn't there the issue of allowing patients to die with dignity? These drugs, just like morphine for cancer patients, will provide some measure of better end-of-life care.” A better scenario might be to have drugs that relieve psychotic symptoms without dangerous side effects. Both Ballard and colleagues and Ashford note that other drugs, such as memantine, antidepressants, selective serotonin reuptake inhibitors, and even low doses of certain antipsychotics may fit the bill, but more research is needed.—Tom Fagan

Comments

Alzheimer patients can be extremely difficult to treat. They can be very dangerous to the caregivers, not to mention the well-documented depression they cause in caregivers.

I know that some clinicians do not think that antipsychotic medications are very effective, but I certainly think they are. I further think that the violent and psychotic patients have more brain damage. Also, violent and psychotic behaviors are very maladaptive and may suggest greater degrees of neuropathology. The pathology, or the maladaptation, likely leads to a higher risk of mortality. Thus, association of medicine use with mortality does not prove causation.

Until I see a study that carefully looks at the neuropathology associated with this increase in mortality of patients receiving antipsychotic medication, I will presume that the patients who are given these drugs actually have a higher risk of mortality and the drugs may actually decrease this risk. In any case, given the severe difficulty with managing patients that leads to the use of such medications, isn't there the issue of allowing patients to die with dignity? These drugs, just like morphine for cancer patients, will provide some measure of better end-of-life care.

Actually, I don't believe that real-life placebo-controlled trials of antipsychotic medications can be conducted, having been involved in many such trials. The most agitated patients need to be managed acutely and cannot participate in such trials. Those who get into such trials probably aren't affected severely enough to warrant the treatment. Looking at placebo discontinuation probably doesn't solve this problem, because dementia patients need to be closely followed over time and have their antipsychotic medications decreased whenever possible, anyway. This issue is noted as a future need, but it has always been just part of appropriate patient care. Antipsychotics are not maintenance medications in this condition; they are for acute management. The need for monitoring and constant medication adjustment could be the best argument for why these drugs really should only be prescribed by those familiar with treating such patients.

There has been some evidence that the use of antipsychotic medications has increased in spite of the black box warning. When a patient is severely agitated, I still think that antipsychotics are the best medication to use.

It should be noted that there is now more experience with trazodone, SSRIs, melatonin, and low doses of the atypical antipsychotic medications, so these patients are a little easier to manage. Further, long-term use of cholinesterase inhibitors and memantine probably decreases the overall behavior problems, though much better research is needed on all of these issues.